Atypical Antipsychotics for Treatment of Schizophrenia Spectrum Disorders

The number of prescriptions for antipsychotic treatment of teenagers has increased sharply in office-based medical practice.¹ Adolescents with psychotic symptoms frequently present for clinical evaluation, and early-onset schizophrenia spectrum disorders (onset of psychotic symptoms before the age of 18 years) represent an important consideration in the differential diagnosis in these youths. The onset of schizophrenia occurs by the age of 19 in nearly 40% of male patients and 23% of female patients.² Although childhood-onset schizophrenia (onset of psychotic symptoms before age 13) is rare,³ the incidence of schizophrenia rises sharply and steadily after the onset of puberty.⁴ Since a longer duration of untreated psychosis may be a predictor of poor outcomes in first-episode psychosis, early and appropriate treatment is crucial.⁵

The goals of antipsychotic treatment for psychotic episodes are amelioration of acute symptoms; main- tenance of treatment effect; and functional recovery in terms of academics, peer relations, and family life. Although antipsychotic medications remain the cornerstone of treatment for early-onset schizophrenia spectrum disorders, most teenagers require multiple treatment strategies to facilitate rehabilitation, including individual supportive therapy, family psychoeducation, and special classroom placement. These interventions help prevent relapse, enhance treatment adherence, and address deficits in social skills. In addition, once acute psychotic symptoms have resolved, comorbid conditions (eg, substance use) must be addressed, as well as other psychosocial factors that contribute to psychiatric morbidity.⁶

The atypical antipsychotics, which differ from typical antipsychotics because of a decrease in associated extrapyramidal symptoms (EPS), have now become the standard treatment for youth with early-onset schizophrenia spectrum disorders.⁷ For years now, these medications have been given to younger people without specific FDA approval for pediatric populations, and clinicians have provided off-label prescriptions drawing from clinical experience using these medications successfully in adults. However, 3 recently completed double-blind, randomized controlled clin- ical trials reporting the use of risperidone, olanzapine, and aripiprazole for early-onset schizophrenia spectrum disorders in teenagers have demonstrated effectiveness relative to placebo.^8-10 As a result of these studies, risperidone and aripiprazole now have a formal indication for the treatment of psychotic symptoms in adolescents with schizophrenia. Several important adverse effects are common with the use of atypical antipsychotics including sedation, metabolic abnormalities, elevated prolactin levels, and movement disorders.

This article reviews the available efficacy and safety data for each atypical antipsychotic. A discussion of the considerations involved in choosing an atypical antipsychotic for this population follows (Table).

Clozapine

The first atypical antipsychotic to be approved by the FDA, clozapine is known for its exceptional efficacy and for its considerable associated adverse effects. Although clozapine is not approved for use in pediatric patients, early studies of this medication in youths with early-onset schizophrenia spectrum disorders suggested that it is effective in that group.^11,12 Because it is associated with risks of neutropenia and agranulocytosis, treatment with clozapine is reserved for children and adolescents with treatment-resistant schizophrenia.¹³ Two initial open-label trials of clozapine treatment in youths demonstrated efficacy with mean dosages of 370 mg/d¹⁴ and 227 mg/d.¹⁵

The first randomized controlled trial of clozapine in pediatric patients compared clozapine with haloperidol in adolescent inpatients with treatment-refractory schizophrenia.¹⁶ In this study, initial dosages were based on weight and ranged from 6.25 to 25 mg/d, and were titrated every 3 days by 1 or 2 times the initial dose. The final mean dosage was 176 mg/d. The investigators reported that although clozapine was superior in efficacy to haloperidol, it was associated with adverse effects including neutropenia, which required 1 patient to discontinue the study. Other notable adverse effects observed in patients taking clozapine included hypotension and dizziness, sialorrhea, seizures, and myocarditis.

Risperidone

Risperidone was the first atypical antipsychotic to be released as a first-line agent in the United States and will soon be available in generic form. The most frequently prescribed antipsychotic agent for children and adolescents, risperidone has now been approved by the FDA for the treatment of schizophrenia in adolescents as well as for autistic spectrum disorders in children. After it was introduced in the United States in 1993, early studies using this medication in children and adolescents with early-onset schizophrenia spectrum disorders suggested that risperidone is effective in reducing psychotic symptoms in this group but that it is associated with adverse effects including moderate weight gain, mild sedation, and dose-related EPS.^17-19 In the study by Armenteros and colleagues,¹⁷ 10 adolescents with schizophrenia were treated for 6 weeks beginning with 1 mg bid and increasing by 1 mg to a maximum daily dose of 10 mg. Six of the patients showed significant reduction of symptoms overall, and although adverse motor effects developed in 5 patients, the medication was thought to be generally well-tolerated.

Efficacy of risperidone for the treatment of schizophrenia in adolescents has now been established. Haas and colleagues⁸ studied 160 adolescents with schizophrenia (aged 13 to 17 years) who were randomized to either 6 weeks of treatment with risperidone (1 to 3 mg/d or 4 to 6 mg/d) or placebo. At the end of the study, improvements in treatment outcomes (eg, Positive and Negative Syndrome Scale [PANSS] total, positive and negative symptom subscale scores) were significantly greater in both risperidone groups than in those who received placebo, and there were few observed differences in efficacy between the active treatment groups. However, the higher-dose group had a greater incidence of EPS and dizziness than the lower-dose group.

Overall, the findings indicate that risperidone is effective in the treatment of early-onset schizophrenia spectrum disorders in adolescents, although it is associated with risks of adverse effects such as movement disorders (possibly at an increased rate compared with adults),²⁰ prolactin elevation,²¹ and significant weight gain. Although prolactin elevation has been repeatedly described for youths treated with risperidone, the available data do not suggest that these changes interfere with development in puberty.²²

Olanzapine

The next atypical antipsychotic introduced in the United States was olanzapine. Pharmacokinetic data for olanzapine use in adolescents suggest that its effect on metabolism is similar to that in adults.²³ Initial studies assessing the use of olanzapine in youth focused on treatment-resistant schizophrenia. In addition, a growing body of research, including case series,²⁴ chart reviews,²⁵ and open-label prospective trials,²⁶ has investigated the use of olanzapine as a first-line treatment option for youth with early-onset schizophrenia spectrum dis- orders. The findings suggest that olanzapine is effective in reducing symptoms in adolescents with these disorders and that it is associated with a low incidence of adverse motor effects.

In a recently completed 6-week, randomized placebo-controlled trial of adolescents with schizophrenia (N = 107), Kryzhanovskaya and colleagues⁹ found olanzapine to be superior to placebo in reducing symptom ratings (ie, overall psychopathology, positive and negative symptoms). In this study, olanzapine was started at 2.5 or 5 mg/d. The titration schedule was flexible, with a final mean dosage of 11.1 mg/d achieved between 4 and 6 weeks. However, patients gained an average of 4.3 kg during this short-term trial, and continued weight gain was observed in patients who enrolled in the 6-month, open-label extension phase. Indeed, among the atypical antipsychotics, olanzapine seems to be associated with a greater risk of weight gain, which limits its practical use. For example, the NIMH Data Safety Monitoring Board stopped enrollment in the olanzapine arm of the Treatment of Early Onset Schizophrenia Spectrum Disorders (TEOSS) study after an interim analysis revealed alarming levels of weight gain and metabolic changes in children treated with olanzapine.²⁷ Although the findings of a recent study indicated that orally disintegrating olanzapine induces less weight gain in adolescents than standard oral tablets, the weight gain still remained in excess of what was seen for youth treated with risperidone.²⁸

Quetiapine

After quetiapine received its initial indication from the FDA for treatment of schizophrenia in 1997, several stud- ies assessing its use in pediatric populations have been conducted. Early data suggested that it is a helpful and well-tolerated medication for children and adolescents with a variety of psychiatric disorders.²⁹ In the first open-label study that assessed the use of quetiapine in adolescents with psychotic disorders, McConville and colleagues³⁰ demonstrated efficacy and tolerability in a 23-day trial in which 10 adolescents with psychotic disorders were given quetiapine 25 mg bid, with upward titration to 400 mg bid by day 20. The investigators found the drug to be well-tolerated and reported an average mean weight gain of 1.5 kg. Pharmacokinetic studies were also undertaken and showed that adolescents and adults have similar metabolism of this medication.

In an open-label extension of this trial, patients were treated with a physician's choice flexible dose titration, with ending dosages ranging from 300 to 800 mg/d. The investigators reported a significant decrease in psychotic symptoms, as well as a nonsignificant increase in weight after 6 weeks.³¹

Shaw and colleagues³² conducted an open-label, 6-week trial using quetiapine to treat psychotic disorders in children and adolescents with an average final treatment dosage of 467 mg/d. They found the drug to be well-tolerated, with the exception of weight gain of 4.1 kg on average.

Randomized controlled data supporting the use of quetiapine in teenagers with schizophrenia are not yet available. Other adverse effects noted in the use of quetiapine include sedation, hypotension, and dizziness. Studies have suggested that the incidence of treatment-emergent movement disorders in adult patients given a daily dose ranging from 50 to 750 mg does not differ from that seen with placebo.³³

Ziprasidone

Ziprasidone was approved for use in the United States in 2001 for the treatment of schizophrenia in adults; it now also has an indication for adult bipolar mania. Efficacy and tolerability have been demonstrated in pediatric patients with Tourette syndrome³⁴ and autistic disorders,³⁵ but there are few data regarding its use in children and adolescents with early-onset schizophrenia spectrum disorders. Single-dose pharmacokinetics and the safety of ziprasidone in children and adolescents have been examined in an open-label study that reported findings that were comparable to those in adults.³⁶ Prompted by concerns about QT prolongation from the adult trials, prospective data have been generated in children and adolescents, which suggested that long-term treatment with low-dose (40 mg) ziprasidone led to prolongation of the QT interval by 28 ± 28 milliseconds.³⁷ Cardiac monitoring according to guidelines recommended by the American Heart Association is advised.³⁸

Aripiprazole

The most recent atypical antipsychotic to become available in the United States is aripiprazole, a high-affinity partial dopamine D₂ agonist, serotonin 5-HT_1A agonist, and 5-HT_2A antagonist.³⁹ Large-scale, pivotal trials with aripiprazole for adults with chronic schizophrenia have consistently shown efficacy, with relatively minor adverse effects on body weight, metabolic parameters, prolactin levels, and sedation.^40-42

Since aripiprazole is newer in the United States, there are fewer data that assess this drug in young patients. However, one randomized controlled trial has recently been completed, which led to the approval of aripiprazole in the treatment of adolescents with schizophrenia. Robb and colleagues¹⁰ studied 300 adolescents with schizophrenia (aged 13 to 17 years) who were randomized to either 6 weeks of active treatment with fixed dosages of aripiprazole (10 or 30 mg/d) or placebo. More than 85% of patients completed the 6-week study. At the end of the study, both the 10 mg and 30 mg doses showed significant differences from placebo on the PANSS total score and several secondary end points. Across treatment outcome measures, however, efficacy tended to be greater at 30 mg than at 10 mg, with earlier evidence of statistical separation from placebo and numerically greater improvements from baseline.

The majority of spontaneously reported adverse effects were EPS, including akathisia and somnolence, which were rated as either mild or moderate in severity.¹³ Mean change in weight from baseline was minimal (10 mg, no change; 30 mg, 0.2 kg; placebo, 20.8 kg). Also, a mean decrease in prolactin levels from baseline to end of study was observed in all treatment groups (10 mg, 212 ng/ mL; 30 mg, 217 ng/mL; placebo, 29 ng/mL). These data suggest that the incidence of weight gain and hyperprolactinemia is likely to be minimal in youths receiving aripiprazole.

First-line therapy

Clinicians can now begin to draw from emerging data to guide them in the choice of atypical antipsychotics for teenagers with early-onset schizophrenia spectrum disorders. A recent open-label, randomized comparison between olanzapine (mean dosage, 8.2 mg/d) and risperidone (mean dosage, 1.6 mg/d) in 25 children with early-onset schizophrenia spectrum disorders found that both medications were comparably efficacious in decreasing symptoms, and both were associated with a similar number of adverse effects, the most important being weight gain.⁴³ Olanzapine had a nonsignificantly lower dropout rate. A recent chart review noted increased EPS in risperidone versus olanzapine and quetiapine.⁴⁴

Efficacy and tolerability of risperidone, olanzapine, and haloperidol were compared in youths with psychosis in a randomized controlled comparative trial.⁴⁵ In this study, all treatments led to a significant reduction of psychotic symptoms. Olanzapine showed the greatest efficacy followed by risperidone and then haloperidol. As expected, the primary adverse effects were sedation, EPS, and weight gain.

The sparsity of controlled trial data on the comparative effectiveness and safety of the atypical antipsychotics in adolescents represents a significant gap in our current knowledge. Only the TEOSS study funded by NIMH has directly compared first-line treatment with risperidone and olanzapine versus a first-generation antipsychotic (molindone) in a large group of adolescents with schizophrenia spectrum disorders.^27,46 However, data from this study are still unavailable. In the face of limited comparative efficacy data, the choice of antipsychotics for teenage patients with early-onset schizophrenia spectrum disorders depends largely on consideration of what is known about the adverse effect profile for each medication.

Treatment-resistant schizophrenia

Since a substantial number of patients do not respond to first-line medication, considerable research has been devoted to assessing options for managing patients with treatment-resistant schizophrenia, defined as failure of 2 or more first-line antipsychotics. These studies have focused on clozapine and olanzapine. An early retrospective study found olanzapine to be an effective substitute for clozapine in adolescents with treatment-resistant schizophrenia⁴⁷; however, in an open-label comparison in a similar population, Kumra and colleagues⁴⁸ observed that olanzapine was effective but inferior in efficacy to clozapine.

More recently, an open-label study found olanzapine to cause sustained improvement over 1 year in 8 of 9 children with treatment-resistant schizophrenia.⁴⁹ Two double-blind, randomized trials that compared clozapine with olanzapine for youths with treatment-resistant schizophrenia have now been published. In the first, Shaw and colleagues⁵⁰ reported that clozapine (mean final dosage, 327 mg/d) was significantly superior in efficacy to olanzapine (mean final dosage, 19.1 mg/d) after 8 weeks, although olanzapine was associated with fewer adverse effects. A recent 12-week, randomized, double-blind comparison between clozapine and high-dose olanzapine in refractory early-onset schizophrenia showed that clozapine (mean final dosage, 403.1 mg/d) was superior to olanzapine (mean final dosage, 26.2 mg/d) in reducing psychosis and negative symptoms, but both medications were associated with significant weight gain and related metabolic abnormalities.⁵¹ These findings suggest that clozapine remains the agent of choice in treatment-resistant schizophrenia, despite its significant risks.

Developmental issues

In the treatment of adolescents, it is important to consider potential developmental differences of this group that may impact course and treatment response. Compared with adult-onset schizophrenia, naturalistic data suggest that the course of illness is more severe in early-onset illness.^52,53 Study findings have suggested that youth treated with antipsychotic medications may be more sensitive to EPS.⁵⁴ In addition, olanzapine may be more sedating in children and adolescents compared with adults.⁵⁵ In light of recent data that suggest that risperidone may have adverse effects on spatial working memory in adults with first-episode schizophrenia, the long-term safety of atypical antipsychotics on the developing brain needs to be clarified.⁵⁶

Conclusion

A growing body of research assessing the use of atypical antipsychotics in adolescents with early-onset schizophrenia spectrum disorders suggests that medications are effective in reducing symptoms and improving function. Although these medications are associated with a lower incidence of adverse motor effects compared with typical antipsychotics, the atypical antipsychotics are associated with a number of important adverse effects including sedation and metabolic abnormalities. Furthermore, increasing evidence suggests that because of developmental differences, adolescents may be especially vulnerable to a whole range of adverse effects. While a limited data set is available that suggests some differences between atypical antipsychotics in terms of their adverse-effect profiles, additional comparative studies of the efficacy and tolerability of atypical antipsychotics are needed to inform the clinician's choice of initial antipsychotic.

Of the adverse effects associated with atypical antipsychotics, metabolic effects may be the most significant problem. Weight gain is of primary importance for teenagers: it contributes to subjective distress and nonadherence and has long-term medical consequences.⁵⁷ The atypical antipsychotics share a class warning for hyperglycemia and, thus, symptoms of diabetes and fasting blood sugars need to be monitored.^58,59

Given that patients with schizophrenia are approximately twice as likely as the general population to die of cardiovascular disease,⁶⁰ and that most of them will require long-term therapy, their physical health must be safeguarded. At the same time, because longer duration of untreated psychosis may predict poorer long-term outcomes in first-episode psychosis, physicians are compelled to treat early and aggressively to improve outcomes for their young patients with early-onset schizophrenia spectrum disorders.⁵

Fortunately, considerable research has been devoted in recent years to begin to characterize the mechanism of these problems, which will hopefully guide interventions to decrease adverse effects. A recent study by Klein and colleagues⁶¹ demonstrated reduced weight gain in adolescents treated with olanzapine while taking metformin, but further research is needed to guide clinicians in managing these difficulties.

In conjunction with medication management of youths with early- onset schizophrenia spectrum disorders, it is important to keep in mind the social contextual issues that commonly occur in this population. There is often confusion and fear in the family regarding the nature of the illness and presenting symptoms that may delay treatment seeking. Shock and denial regarding the diagnosis commonly emerge during the early treatment phase. Since treatment noncompliance or discontinuation is a significant concern, early psychoeducation and support is crucial.

In addition, since response to currently available treatments remains suboptimal for many teenagers with schizophrenia, it is important to examine whether the use of adjunctive psychosocial treatments improves outcome.

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